Advanced Stage Prostate Cancer Research Articles

Role of solute carrier transporters SLC25A17 and SLC27A6 in acquired resistance to enzalutamide in castration-resistant prostate cancer.

Enzalutamide (XTANDI®), an antiandrogen, is used for the treatment of advanced-stage prostate cancer. Approximately, 60% of patients receiving enzalutamide show initial remission followed by disease relapse with the emergence of highly aggressive castration-resistant prostate cancer. Solute carrier (SLC) proteins play a critical role in the development of drug resistance by altering cellular metabolism. Transcriptome analysis revealed the predominance of SLC25A17 and SLC27A6 in enzalutamide-resistant prostate cancer cells; however, their role in antiandrogen resistance has not been elucidated. sgRNA-mediated knockdown of SLC25A17 and SLC27A6 suppressed cell proliferation and migration in enzalutamide-resistant cells. An induction of G1/S cell cycle arrest and abundance of hypo-diploid cells along with the reduction in the protein expression CyclinD1 and CDK6, the checkpoint factors, was observed including increased cell death as evident by BAX upregulation in knockdown cells. Inhibition of SLC25A17 and SLC27A6 resulted in downregulation of fatty acid synthase and acetyl-CoA carboxylase with parallel decrease in the levels of lactic acid in enzalutamide resistant cells. However, downregulation of triglyceride and citric acid was only observed in SLC25A17 silenced cells. The protein-protein interaction of SLC25A17 and SLC27A6 revealed alteration in some common drug-resistant and metabolism-related genes. Analysis of The Cancer Genome Atlas database exhibiting high SLC25A17 and SLC27A6 gene expression in prostate cancer patients were associated with poor survival than those with low expression of these proteins. In conclusion, SLC25A17 and SLC27A6 and its interactive network play an essential role in the development of enzalutamide resistance through metabolic reprogramming and may be identified as therapeutic target(s) to circumvent drug resistance.

Multicenter External Validation of a Nomogram for Predicting Positive Prostate-specific Membrane Antigen/Positron Emission Tomography Scan in Patients with Prostate Cancer Recurrence

BackgroundA nomogram has recently been developed to predict 68Ga-labeled prostate-specific membrane antigen (PSMA)-11 positron emission tomography (PET)/computed tomography (PSMA-PET) results in recurrent prostate cancer (PCa) patients. ObjectiveTo perform external validation of the original nomogram in a multicentric setting. Design, setting, and participantsA total of 1639 patients who underwent PSMA-PET for prostate-specific antigen (PSA) relapse after radical therapy were retrospectively included from six high-volume PET centers. The external cohort was stratified according to clinical setting categories: group 1: first-time biochemical recurrence (n = 774); group 2: PSA relapse after salvage therapy (n = 499); group-3: biochemical persistence after radical prostatectomy (n = 210); and group-4: advanced-stage PCa before second-line systemic therapies (n = 124). InterventionPSMA-PET in recurrent PCa. Outcome measurements and statistical analysisPSMA-PET detection rate was assessed in the overall population and in each subgroup. A multivariable logistic regression model was produced to evaluate the predictors of a positive scan. The performance characteristics of the model were assessed by quantifying the predictive accuracy (PA) according to model calibration. The Youden’s index was used to find the best nomogram’s cutoff. Decision curve analysis (DCA) was implemented to quantify the nomogram’s clinical net benefit. Results and limitationsIn the external cohort, the overall detection rate was 53.8% versus 51.2% in the original population. At multivariate analysis, International Society of Urological Pathology grade group, PSA, PSA doubling time, and clinical setting were independent predictors of a positive scan (all p ≤ 0.02). The PA of the nomogram was identical to the original model (82.0%); the model showed an optimal calibration curve. The best nomogram’s cutoff was 55%. In the DCA, the nomogram revealed clinical net benefit when the threshold nomogram probabilities were ≥20%. The retrospective design is a major limitation. ConclusionsThe original nomogram exhibited excellent characteristics on external validation. The incidence of a false negative scan can be reduced if PSMA-PET is performed when the predicted probability is ≥20%. Patient summaryA nomogram has been developed to predict prostate-specific membrane antigen/positron emission tomography (PSMA-PET) results for recurrent prostate cancer (PCa). The nomogram represents an easy tool in the decision-making process of recurrent PCa.

Loss of microRNA-135b Enhances Bone Metastasis in Prostate Cancer and Predicts Aggressiveness in Human Prostate Samples.

Simple SummaryProstate cancer (PCa) is the most prevalent cancer in males worldwide, and it was the fifth leading cause of cancer mortality in this group in 2020. Near 70% of advanced-stage PCa patients will undergo bone metastasis, suffering pathological complications that severely affect patients’ quality of life and probably progress in most cases to lethal PCa. Our main objective was to unveil novel molecules associated with choosing the bone as a metastatic niche. For this purpose, we generated and characterized a cell line with increased tropism to bone. Its molecular analysis has led us to identify factors with a potential role in bone metastasis that could also be used as biomarkers of disease progression. These data help us to understand the mechanisms that increase bone metastasis penetrance of PCa cells and could provide new therapeutic tools in the future for patients with worse prognoses.About 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients’ quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone tropism is crucial. For this purpose, we generated an animal model with high penetrance to metastasize to bone using an intracardiac percutaneous injection of PC3 cells to identify PCa metastasis-promoting factors. Using genomic high-throughput analysis we identified a miRNA signature involved in bone metastasis that also presents potential as a biomarker of PCa progression in human samples. In particular, the downregulation of miR-135b favored the incidence of bone metastases by significantly increasing PCa cells’ migratory capacity. Moreover, the PLAG1, JAKMIP2, PDGFA, and VTI1b target genes were identified as potential mediators of miR-135b’s role in the dissemination to bone. In this study, we provide a genomic signature involved in PCa bone growth, contributing to a better understanding of the mechanisms responsible for this process. In the future, our results could ultimately translate into promising new therapeutic targets for the treatment of lethal PCa.

Comparison of 68Ga-Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography Computed Tomography (PET-CT) and Whole-Body Magnetic Resonance Imaging (WB-MRI) with Diffusion Sequences (DWI) in the Staging of Advanced Prostate Cancer.

Simple SummaryPrecise staging is key for the optimal management of advanced prostate cancer. PSMA PET-CT and WB-MRI outperform standard imaging technology for staging high-risk prostate cancer, but direct comparison between both modalities is lacking. The primary endpoint of our study was to compare the diagnostic accuracy of both techniques in the detection of lymph node, bone and visceral metastases against a best valuable comparator (BVC), defined as a consensus adjudication of all lesions on the basis of baseline and follow-up imaging, biological and clinical data and histopathologic confirmation when available. Knowing the diagnostic accuracy of both next generation imaging modalities might influence the diagnostic and therapeutic strategy in prostate cancer by tailoring therapy. However, the impact on treatment and patient outcome of an improved detection of metastases has not been determined yet.Background: Prostate specific membrane antigen (PSMA) positron emission tomography computed tomography (PET-CT) and whole-body magnetic resonance imaging (WB-MRI) outperform standard imaging technology for the detection of metastasis in prostate cancer (PCa). There are few direct comparisons between both modalities. This paper compares the diagnostic accuracy of PSMA PET-CT and WB-MRI for the detection of metastasis in PCa. One hundred thirty-four patients with newly diagnosed PCa (n = 81) or biochemical recurrence after curative treatment (n = 53) with high-risk features prospectively underwent PSMA PET-CT and WB-MRI. The diagnostic accuracy of both techniques for lymph node, skeletal and visceral metastases was compared against a best valuable comparator (BVC). Overall, no significant difference was detected between PSMA PET-CT and WB-MRI to identify metastatic patients when considering lymph nodes, skeletal and visceral metastases together (AUC = 0.96 (0.92–0.99) vs. 0.90 (0.85–0.95); p = 0.09). PSMA PET-CT, however, outperformed WB-MRI in the subgroup of patients with newly diagnosed PCa for the detection of lymph node metastases (AUC = 0.96 (0.92–0.99) vs. 0.86 (0.79–0.92); p = 0.0096). In conclusion, PSMA PET-CT outperforms WB-MRI for the detection of nodal metastases in primary staging of PCa.

Concomitant High Apoptosis Inhibitor of Macrophage (AIM) and Low Prostate-Specific Antigen (PSA) Indicates Activated T Cell-Mediated Anticancer Immunity, Enhance Sensitivity to Pembrolizumab, and Elicit Good Prognosis in Prostate Cancer.

Background: Despite its widespread use, the use of prostate-specific antigen (PSA) alone as a screening biomarker for prostate cancer (PCa) leads often to unwarranted prostate biopsy, over-diagnosis, and consequently, over-treatment, because of its limited specificity. There are reports that the apoptosis inhibitor of macrophage (AIM), secreted mainly by macrophages and epithelial cells, is upregulated during inflammation and facilitates immune recognition of cancerous cells by blocking human regulator of complement activation. Objective: These controversies around the PSA utility necessitate a reexamination of its use as a screening tool. More so, despite the suggested implication of AIM in anticancer immunosurveillance, there is a dearth of information on its role in therapy response, disease progression, and clinical outcomes of patients with PCa. These inform the present study to probe the nature and role of AIM/PSA signaling in anticancer immunity and prognosis in PCa. Methods: A combination of bioinformatics-aided statistical analyses, gene function annotation, and immune infiltrate analyses, coupled with tissue staining, and function assays, namely migration, invasion, and clonogenicity assays, we employed. Results: We demonstrated that AIM and PSA expression levels are inversely correlated in PCa clinical samples and cell lines, with AIMlowPSAhigh defining PCa, compared to AIMhighPSAlow in normal samples. Concomitant aberrant PSA and significantly suppressed AIM expression levels positively correlated with high-grade disease and characterized by advanced stage prostate cancer, regardless of mutation status. We found that a high PSA/AIM ratio is associated with disease recurrence in patients with prostate cancer but is equivocal for overall survival. In addition, PSA-associated AIM suppression is implicated in the enhanced ‘metastability’ of PCa and a high AIM/PSA ratio is associated with strong castration-induced regression. CRISPR-mediated AIM knockout was associated with higher PSA expression while ectopic expression of AIM significantly attenuated the migration and invasive capability of PC3 and DU145 cells. Interestingly, compared to normal samples, we observed that AIM, biomarkers of T-cell activation and M1 phenotype markers are co-suppressed in PCa samples. Conclusion: Herein, we demonstrate that AIM/CD5L binds to PSA and that a high PSA/AIM ratio defines advanced stage PCa (regardless of mutation status), is implicated in enhanced metastability, and associated with disease recurrence, while a high AIM/PSA ratio is associated with strong castration-induced regression. More so, the ectopic expression of AIM significantly enhances the anticancer effect of Pembrolizumab and elicits an increased CD8+ T-cell count in AIMhiPSAloPDL1+ PCa cases that are respondent to Pembrolizumab treatment.

Effects of 225Ac-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis.

Prostate-specific membrane antigen (PSMA), overexpressed in prostate cancer, has become a popular target for radionuclide-based theranostic applications in the advanced stages of prostate cancer. We conducted a meta-analysis of the therapeutic effects of PSMA-targeting α-therapy (225Ac-PSMA radioligand therapy [RLT]) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: A systematic search was performed using the keywords "mCRPC," "225Ac-PSMA," and "alpha therapy." Therapeutic responses were analyzed as the pooled proportions of patients with more than a 50% prostate-specific antigen (PSA) decline and any PSA decline. Survival outcomes were analyzed by estimating summary survival curves for progression-free survival and overall survival. Adverse events were analyzed as the pooled proportions of patients with xerostomia and severe hematotoxicity (anemia, leukocytopenia, and thrombocytopenia). Results: Nine studies with 263 patients were included in our meta-analysis. The pooled proportions of patients with more than a 50% PSA decline and any PSA decline were 60.99% (95% CI, 54.92%-66.83%) and 83.57% (95% CI, 78.62%-87.77%), respectively. The estimated mean progression-free survival and mean overall survival were 9.15 mo (95% CI, 6.69-11.03 mo) and 11.77 mo (95% CI, 9.51-13.49 mo), respectively. The pooled proportions of patients with adverse events were 62.81% (95% CI, 39.34%-83.46%) for xerostomia, 14.39% (95% CI, 7.76%-22.63%) for anemia, 4.12% (95% CI, 0.97%-9.31%) for leukocytopenia, and 7.18% (95% CI, 2.70%-13.57%) for thrombocytopenia. Conclusion: In our study, around 61% of patients had more than a 50% PSA decline and 84% of patients had any PSA decline after 225Ac-PSMA RLT. The common adverse events in 225Ac-PSMA RLT were xerostomia in 63% of patients and severe hematotoxicity in 4%-14% of patients.

A New Approach for Prostate Cancer Diagnosis by miRNA Profiling of Prostate-Derived Plasma Small Extracellular Vesicles.

Vesicular miRNA has emerged as a promising marker for various types of cancer, including prostate cancer (PC). In the advanced stage of PC, the cancer-cell-derived small extracellular vesicles (SEVs) may constitute a significant portion of circulating vesicles and may mediate a detectable change in the plasma vesicular miRNA profile. However, SEVs secreted by small tumor in the prostate gland constitute a tiny fraction of circulating vesicles and cause undetectable miRNA pattern changes. Thus, the isolation and miRNA profiling of a specific prostate-derived fraction of SEVs can improve the diagnostic potency of the methods based on vesicular miRNA analysis. Prostate-specific membrane antigen (PSMA) was selected as a marker of prostate-derived SEVs. Super-paramagnetic beads (SPMBs) were functionalized by PSMA-binding DNA aptamer (PSMA–Apt) via a click reaction. The efficacy of SPMB–PSMA–Apt complex formation and PSMA(+)SEVs capture were assayed by flow cytometry. miRNA was isolated from the total population of SEVs and PSMA(+)SEVs of PC patients (n = 55) and healthy donors (n = 30). Four PC-related miRNAs (miR-145, miR-451a, miR-143, and miR-221) were assayed by RT-PCR. The click chemistry allowed fixing DNA aptamers onto the surface of SPMB with an efficacy of up to 89.9%. The developed method more effectively isolates PSMA(+)SEVs than relevant antibody-based technology. The analysis of PC-related miRNA in the fraction of PSMA(+)SEVs was more sensitive and revealed distinct diagnostic potency (AUC: miR-145, 0.76; miR-221, 0.7; miR-451a, 0.65; and miR-141, 0.64) than analysis of the total SEV population. Thus, isolation of prostate-specific SEVs followed by analysis of vesicular miRNA might be a promising PC diagnosis method.

PD65-06 THE EFFECT OF PROSTATE CANCER SCREENING GUIDELINE CHANGES ON STAGE MIGRATION OF PROSTATE CANCER IN AUSTRALIA

You have accessJournal of UrologyProstate Cancer: Detection & Screening VII (PD65)1 Sep 2021PD65-06 THE EFFECT OF PROSTATE CANCER SCREENING GUIDELINE CHANGES ON STAGE MIGRATION OF PROSTATE CANCER IN AUSTRALIA Jonathan Kam, Venu Chalasani, Ahmed Goolam, Philip Bergersen, Melanie Edwards, Warwick Delprado, and Max Dias Jonathan KamJonathan Kam More articles by this author , Venu ChalasaniVenu Chalasani More articles by this author , Ahmed GoolamAhmed Goolam More articles by this author , Philip BergersenPhilip Bergersen More articles by this author , Melanie EdwardsMelanie Edwards More articles by this author , Warwick DelpradoWarwick Delprado More articles by this author , and Max DiasMax Dias More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002109.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A decrease in PSA testing and corresponding increase in diagnosis of advanced stage prostate cancer in the US has been linked to the USPSTF guidelines which recommended against prostate cancer screening in 2012. Screening guidelines by the Royal Australasian College of GPs recommended against prostate cancer screening in their 2009, 2012 and 2016 guidelines. There is no published data analysing the trends of prostate cancer testing and stage in Australia over this period. We aimed to determine if screening guidelines have resulted in decreasing PSA testing and a migration to more advanced stage prostate cancer in New South Wales (NSW), the largest state of Australia. METHODS: Patients undergoing radical prostatectomy in NSW between 2007-2018 were identified in our prospectively maintained database. PSA testing and radical prostatectomy rates were obtained from Medicare Statistics database. Population data was obtained from Australian Bureau of Statistics. Joinpoint regression analysis was performed to analyse trends. RESULTS: We identified 17,375 patients who underwent radical prostatectomy in our database, representing 69% of radical prostatectomies in NSW. The rates of non-organ confined disease (pT3) significantly increased from 31% to 55%, annual percentage change (APC) 5.36%, p<0.05. This was seen in both pT3a stage (extra-capsular extension), APC 5.41%, p<0.05 and pT3b stages (seminal vesicle invasion), APC 4.6%, p<0.05. There was a significant decrease in the rate of PSA testing being performed in NSW, APC -4.9%, p<0.05 with crude testing rates decreasing from 8342 to 4910 per 100,000 males. CONCLUSIONS: A significant decrease in PSA testing in NSW has been observed from 2007 to 2018 corresponding to a significant increase in more advanced disease being found at time of radical prostatectomy. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1154-e1154 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jonathan Kam More articles by this author Venu Chalasani More articles by this author Ahmed Goolam More articles by this author Philip Bergersen More articles by this author Melanie Edwards More articles by this author Warwick Delprado More articles by this author Max Dias More articles by this author Expand All Advertisement Loading ...

Longitudinal analysis of individual cfDNA methylome patterns in metastatic prostate cancer

BackgroundDisease progression and therapeutic resistance are hallmarks of advanced stage prostate cancer (PCa), which remains a major cause of cancer-related mortality around the world. Longitudinal studies, coupled with the use of liquid biopsies, offer a potentially new and minimally invasive platform to study the dynamics of tumour progression. Our aim was to investigate the dynamics of personal DNA methylomic profiles of metastatic PCa (mPCa) patients, during disease progression and therapy administration.ResultsForty-eight plasma samples from 9 mPCa patients were collected, longitudinally, over 13–21 months. After circulating cell-free DNA (cfDNA) isolation, DNA methylation was profiled using the Infinium MethylationEPIC BeadChip. The top 5% most variable probes across time, within each individual, were utilised to study dynamic methylation patterns during disease progression and therapeutic response. Statistical testing was carried out to identify differentially methylated genes (DMGs) in cfDNA, which were subsequently validated in two independent mPCa (cfDNA and FFPE tissue) cohorts. Individual cfDNA global methylation patterns were temporally stable throughout the disease course. However, a proportion of CpG sites presented a dynamic temporal pattern that was consistent with clinical events, including different therapies, and were prominently associated with genes linked to immune response pathways. Additionally, study of the tumour fraction of cfDNA identified > 2000 DMGs with dynamic methylation patterns.ConclusionsLongitudinal assessment of cfDNA methylation in mPCa patients unveiled dynamic patterns associated with disease progression and therapy administration, thus highlighting the potential of using liquid biopsies to study PCa evolution at a methylomic level.

Abstract 1915: Novel synthetic DNA vaccines in prostate cancer immunotherapy

Abstract Prostate cancer (PCa) represents the most predominant cancer type among males with an estimated 191,930 cases diagnosed in 2020 with 33,330 deaths globally. Notably, different treatment modalities such as surgery, chemo, radiation and hormone therapy exhibited improved outcomes in early stage PCa patients; however, there exist high recurrence rate in the treated patients and leads to castration resistant prostate cancer, the treatment choices for which are highly restricted. This scenario has pressed us to consider synthetic DNA vaccine-based immunotherapy approach, with ability to induce antigen-specific tumor-killing immune cells. Considering the high heterogeneity of prostate cancer cells, we hypothesized that synthetic DNA vaccines targeting multiple prostate specific antigens would elicit improved immune responses in those who are at high risk as well as advanced stages of prostate cancer. Therefore, we generated synthetic enhanced DNA immunogens as DNA constructs (SEV) targeting STEAP1, PAP, PARM1, PSCA, PCTA and PSP94 through utilization of bioinformatics approaches. The SEVs for prostate cancer antigens elicited potent cellular immunity as well as polyfunctionality of antigen-specific T cells in mice. Further, they were capable of generating robust humoral immune responses to each antigen. The anti-tumor activities of the SEVs were studied in prostate tumor which showed that the induced immune responses delayed tumor progression and enhanced infiltration of anti-tumor CD8+ T cells in the tumor microenvironment in a mouse model challenge system. These data highlight further study of these novel immunogens as synthetic DNA immunogens for immunotherapy of PCa, and perhaps other human cancers. Citation Format: Devivasha Bordoloi, Peng Xiao, Hyeree Choi, Michelle Ho, Alfredo Perales-Puchalt, Makan Khoshnejad, J.Joseph Kim, Laurent Humeau, Alagarsamy Srinivasan, David B. Weiner, Kar Muthumani. Novel synthetic DNA vaccines in prostate cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1915.

PCN140 Hospital Competition and Quality of Prostate Cancer Care

Hospital competition is important for addressing the variation in quality and cost. We examined the association of hospital competition with process of care (time to treatment, treatment type) and outcomes (mortality, emergency room (ER) use and cost) in Medicare fee-for-service beneficiaries with prostate cancer. This was a population-based cohort study of Surveillance, Epidemiological, and End Results (SEER)-Medicare data from 1995- 2016, linked with American Medical Association, and American Hospital Association data. Eligible patients were men aged ≥66 years with localized or advanced stage prostate cancer. Hirschman-Herfindahl index was computed for all serving hospitals based on number of competitors, i.e., number of hospitals situated within the hospital referral region. Outcomes were overall and prostate cancer-specific survival, ER visits, and cost. We used Cox proportional hazard models and competing risk models for assessing survival, Poisson models for count data, and GLM (log-link) models for cost data. Propensity score and instrumental variables were used to minimize potential biases. Of 434,264 patients, 85% were localized and 15% were advanced stage. Hospitals within high competition area were more likely to perform surgery, whereas those in low competition area used radiation therapy. Among localized disease patients, low hospital competition was associated with higher hazard of overall mortality (HR=1.08, 95% CI=1.07 - 1.10) and prostate cancer-specific mortality (HR=1.13, 95% CI=1.09 - 1.17), higher odds of ER visits (OR=1.13, 95% CI=1.11 - 1.15), and higher cost (OR=1.18, 95% CI=1.10 – 1.21). Similar results were observed for advanced stage patients. Higher scores on OI were associated with higher total medical costs per capita per year, and not associated with overall mortality. We observed that higher hospital competition is associated with improved quality of care and lower cost among patients with localized or advanced stage prostate cancer. Policy measures should be implemented to improve hospital competition.

The role of testosterone replacement therapy and statin use, and their combination, in prostate cancer.

Previous studies have reported conflicting results in the associations of testosterone replacement therapy (TTh) and statins use with prostate cancer (PCa). However, the combination of these treatments with PCa stage and grade at diagnosis and prostate cancer-specific mortality (PCSM) and by race/ethnicity remains unclear. We identified non-Hispanic White (NHW, N = 58,576), non-Hispanic Black (NHB, n = 9,703) and Hispanic (n = 4,898) men diagnosed with PCa in SEER-Medicare data 2007-2011. Pre-diagnostic prescription of TTh and statins was ascertained for this analysis. Multivariable-adjusted logistic and Cox proportional hazards models were used to evaluate the association of TTh and statins use with PCa stage and grade and PCSM. 22.5% used statins alone, 1.2% used TTh alone, and 0.8% used both. TTh and statins were independently, inversely associated with PCa advanced stage and high grade. TTh plus statins was associated with 44% lower odds of advanced stage PCa (OR 0.56, 95% CI 0.35-0.91). As expected, similar inverse associations were present in NHWs as the overall cohort is mostly comprised NHW men. In Hispanic men, statin use with or without TTh was inversely associated with aggressive PCa. Pre-diagnostic use of TTh or statins, independent or in combination, was inversely associated with aggressive PCa, including in NHW and Hispanics men, but was not with PCSM. The findings for use of statins with aggressive PCa are consistent with cohort studies. Future prospective studies are needed to explore the independent inverse association of TTh and the combined inverse association of TTh plus statins on fatal PCa.

Tumor-Associated Macrophage Promotes the Survival of Cancer Cells upon Docetaxel Chemotherapy via the CSF1/CSF1R-CXCL12/CXCR4 Axis in Castration-Resistant Prostate Cancer.

Castration-resistant prostate cancer (CRPC) is an advanced stage of prostate cancer that can progress rapidly even in patients treated with castration. Previously, we found that tumor-associated macrophages (TAM) can be recruited by CSF-1 secreted by docetaxel-treated prostate cancer cells and promote the survival of cancer cells in response to chemotherapy. The inhibition of CSF-1R can impede this effect and significantly prolong survival in xenograft mice. However, the actual mechanism of how TAM improves cancer cell survival still remains elusive and controversial. Here, for the first time, we found that the enhanced survival of cancer cells achieved by TAM was mainly mediated by CXCR4 activation from the increased secretion of CXCL12 from CSF-1 activated TAM. This finding helps to clarify the mechanism of chemoresistance for second-line chemotherapy using docetaxel, facilitating the development of novel drugs to overcome immune tolerance in castration-resistant prostate cancer.

Association between environmental quality and prostate cancer stage at diagnosis.

Prostate cancer (PC) etiology is up to 57% heritable, with the remainder attributed to environmental exposures. There are limited studies regarding national level environmental exposures and PC aggressiveness, which was the focus of this study METHODS: SEER was queried to identify PC cases between 2010 and 2014. The environmental quality index (EQI) is a county-level metric for 2000-2005 combining data from 18 sources and reports an overall ambient environmental quality index, as well as 5 environmental quality sub-domains (air, water, land, built, and sociodemographic) with higher values representing lower environmental quality. PC stage at diagnosis was determined and, multivariable logistic regression models which adjusted for age at diagnosis (years) and self-reported race (White, Black, Other, Unknown) were used to test associations between quintiles of EQI scores and advanced PC stage at diagnosis. The study cohort included 252,164 PC cases, of which 92% were localized and 8% metastatic at diagnosis. In the adjusted regression models, overall environmental quality EQI (OR 1.20, CI 1.15-1.26), water EQI (OR: 1.34, CI: 1.27-1.40), land EQI (OR: 1.35, CI: 1.29-1.42) and sociodemographic EQI (OR: 1.29, CI: 1.23-1.35) were associated with metastatic PC at diagnosis. For these domains there was a dose response increase in the OR from the lowest to the highest quintiles of EQI. Black race was found to be an independent predictor of metastatic PC at diagnosis (OR: 1.36, CI: 1.30-1.42) and in stratified analysis by race; overall EQI was more strongly associated with metastatic PC in Black men (OR: 1.53, CI: 1.35-1.72) compared to White men (OR: 1.18, CI: 1.12-1.24). Lower environmental quality was associated with advanced stage PC at diagnosis. The water, land and sociodemographic domains showed the strongest associations. More work should be done to elucidate specific modifiable environmental factors associated with aggressive PC.

A Multi-Center Retrospective Analysis Examining the Effect of Dipeptidyl Peptidase-4 Inhibitors on Progression-Free Survival in Patients With Prostate Cancer.

BackgroundCluster of differentiation 26/dipeptidyl peptidase-4 (DPP4) is a cell surface glycoprotein with multifaceted roles, including immune regulation, glucose metabolism, and tumorigenesis. Recent literature has identified DPP4 inhibitors to improve survival in diabetic patients with prostate cancer. DPP4 inhibitors have been proposed to play a role in prostate cancer, as DPP4 is found at higher levels in malignant prostate tissue compared to benign and correlates with PSA levels and cancer stage. In this multi-center retrospective study, we aim to define the effects of DPP4 inhibitors on progression-free survival (PFS) in diabetic patients with advanced-stage prostate cancer.MethodologyWe performed a retrospective analysis of 161 patients with diabetes and advanced-stage (III or IV) prostate cancer at the University of Florida Health Cancer Center and Moffitt Cancer Center. Our cohort included 120 patients on metformin (control group) and 41 on a DPP4 inhibitor (study group).ResultsNo significant difference in progression of prostate cancer was identified between those on DPP4 inhibitors versus metformin (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.64-1.61; p = 0.955). Median time to progression was 3.5 years (range: 2.4-4.6 years).ConclusionsDespite prior literature indicating survival benefit of DPP4 inhibitors in prostate cancer, our study did not identify a statistically significant improvement of PFS in diabetic patients with advanced prostate cancer. Additional analysis with larger sample sizes and prospective investigation with study of tumor microenvironment are needed to evaluate clinical impact and potential survival benefit of DPP4 inhibitors in prostate cancer.

Independent and Joint Effects of Testosterone Replacement Therapy and Statins use on the Risk of Prostate Cancer Among White, Black, and Hispanic Men.

The associations of testosterone therapy (TTh) and statins use with prostate cancer remain conflicted. However, the joint effects of TTh and statins use on the incidence of prostate cancer, stage and grade at diagnosis, and prostate cancer-specific mortality (PCSM) have not been studied.We identified White (N = 74,181), Black (N = 9,157), and Hispanic (N = 3,313) men diagnosed with prostate cancer in SEER-Medicare 2007-2016. Prediagnostic prescription of TTh and statins was ascertained for this analysis. Weighted multivariable-adjusted conditional logistic and Cox proportional hazards models evaluated the association of TTh and statins with prostate cancer, including statistical interactions between TTh and statins.We found that TTh (OR = 0.74; 95% CI, 0.68-0.81) and statins (OR = 0.77; 95% CI, 0.0.75-0.88) were inversely associated with incident prostate cancer. Similar inverse associations were observed with high-grade and advanced prostate cancer in relation to TTh and statins use. TTh plus statins was inversely associated with incident prostate cancer (OR = 0.53; 95% CI, 0.48-0.60), high-grade (OR = 0.43; 95% CI, 0.37-0.49), and advanced prostate cancer (OR = 0.44; 95% CI, 0.35-0.55). Similar associations were present in White and Black men, but among Hispanics statins were associated with PCSM.Prediagnostic use of TTh or statins, independent or combined, was inversely associated with incident and aggressive prostate cancer overall and in NHW and NHB men. Findings for statins and aggressive prostate cancer are consistent with previous studies. Future studies need to confirm the independent inverse association of TTh and the joint inverse association of TTh plus statins on risk of prostate cancer in understudied populations. PREVENTION RELEVANCE: The study investigates a potential interaction between TTh and statin and its effect on incident and aggressive prostate cancer in men of different racial and ethnic backgrounds. These results suggest that among NHW and non-Hispanic Black men TTh plus statins reduced the odds of incident prostate cancer, high-grade and advance stage prostate cancer.

Unbiased Phenotype-Based Screen Identifies Therapeutic Agents Selective for Metastatic Prostate Cancer.

In American men, prostate cancer is the second leading cause of cancer-related death. Dissemination of prostate cancer cells to distant organs significantly worsens patients’ prognosis, and currently there are no effective treatment options that can cure advanced-stage prostate cancer. In an effort to identify compounds selective for metastatic prostate cancer cells over benign prostate cancer cells or normal prostate epithelial cells, we applied a phenotype-based in vitro drug screening method utilizing multiple prostate cancer cell lines to test 1,120 different compounds from a commercial drug library. Top drug candidates were then examined in multiple mouse xenograft models including subcutaneous tumor growth, experimental lung metastasis, and experimental bone metastasis assays. A subset of compounds including fenbendazole, fluspirilene, clofazimine, niclosamide, and suloctidil showed preferential cytotoxicity and apoptosis towards metastatic prostate cancer cells in vitro and in vivo. The bioavailability of the most discerning agents, especially fenbendazole and albendazole, was improved by formulating as micelles or nanoparticles. The enhanced forms of fenbendazole and albendazole significantly prolonged survival in mice bearing metastases, and albendazole-treated mice displayed significantly longer median survival times than paclitaxel-treated mice. Importantly, these drugs effectively targeted taxane-resistant tumors and bone metastases – two common clinical conditions in patients with aggressive prostate cancer. In summary, we find that metastatic prostate tumor cells differ from benign prostate tumor cells in their sensitivity to certain drug classes. Taken together, our results strongly suggest that albendazole, an anthelmintic medication, may represent a potential adjuvant or neoadjuvant to standard therapy in the treatment of disseminated prostate cancer.

A multicenter retrospective analysis examining the effect of dipeptidyl protease 4 (DPP4) inhibitors on progression-free survival in patients with prostate cancer.

109 Background: Dipeptidyl peptidase IV (DPP4), also known as Cluster of differentiation 26 (CD26) is a commonly expressed cell surface protein found in many cell types that can function as a tumor suppressor or activator, depending on the cancer type its interactions with the tumor microenvironment. DPP4 has been studied as a tumor biomarker due to its expression in various primary tumors and metastases. Recent literature established benefits of DPP4 inhibitors on progression free survival (PFS) of diabetic patients with advanced colorectal and airway cancers. In this study, we examine the effect of DPP4 inhibitors on PFS in diabetic patients (pts) with advanced-stage prostate cancer. Methods: We performed a multi-center retrospective analysis at Moffitt Cancer Center and the University of Florida of diabetic pts with advanced stage (III or IV) prostate cancer. All pts were on anti-hyperglycemic therapy and received either surgery, radiation therapy, or both for their prostate cancer. The control group included pts on metformin and a sulfonylurea, and the study group included pts on a DPP4 inhibitor and metformin. PFS was calculated for both groups, and Cox proportional hazards regression was used to determine statistical significance. Kaplan-Meier survival analysis was done to predict the effect of DPP4 inhibition and radiation therapy on PFS. Results: Our study population consisted of 161 pts, with 120 pts in the control group and 41 in the study group. No significant difference in progression of prostate cancer was found between those on DPP4 inhibitor vs. Metformin. Specifically, 24 of 41 (59%) of patients on DPP4 inhibitors progressed, while 73 of 120 (61%) of patients on Metformin had progression of prostate cancer (HR 1.01, 95% CI 0.64 to 1.61, p= 0.955). Median time to progression was 3.3 years in the DPP4 group versus 3.5 years in the Metformin group. However, radiation therapy was associated with improved PFS (HR 0.56, 95% CI 0.37 to 0.84, p= 0.0006). Conclusions: Contrary to what has been shown in pts with diabetes and advanced colorectal or airway cancers, exposure to DPP4 inhibitors did not lead to statistically significant improvement in PFS in pts with advanced stage prostate cancer. Recent data suggests that DPP4 may act as a tumor suppressor gene to the androgen receptor (AR) pathway, and that DPP4 inhibition can result in emergence of resistance to androgen deprivation therapy (ADT). Further analysis with larger sample sizes is necessary to elucidate if this is applicable to prostate cancer as a whole, or if this effect is specific to castrate-sensitive prostate cancer (CSPC) vs. castrate-resistant prostate cancer (CRPC).

Hospital competition, quality, and cost of prostate cancer care.

235 Background: Hospital competition is important for addressing the disparity in quality and cost of prostate cancer care. Study objective was to examine the association of hospital competition with process of care (time to treatment, treatment and overuse) and outcomes (medial care use, complications, mortality and cost) in Medicare fee-for-service beneficiaries with prostate cancer. Methods: This was a population-based cohort study of Surveillance, Epidemiological, and End Results-Medicare (SEER-Medicare) data from 1995- 2016, linked with American Medical Association for physician data and American Hospital Association for hospital level data. Eligible patients were men 66 years or older with localized or advanced stage prostate cancer at diagnosis. The Hirschman-Herfindahl index (HHI) was computed for all serving hospitals based on number of competitors, i.e., number of hospitals situated within the hospital referral region(HRR). The Overuse Index (OI) was used to composite measure of overuse during treatment (one year after diagnosis) and follow-up care phase. Outcomes were overall and prostate cancer-specific survival, complications, readmissions, ER visits, and cost. We used survival analysis, including competing risk analysis, Poisson (zero inflated) models for count data, and GLM (log-link) models for cost data. Propensity score and instrumental variable approaches were used to minimize potential biases. Results: In our study cohort of 434,264, 85% of patients had localized disease stage, and 15% had advanced stage. For both localized and advanced stage groups, age, race and ethnicity, geographic region, comorbidity, socio-economic status, and primary treatment differed by hospital competition (high competition vs. low competition). Hospitals within high competition area were more likely to perform surgery, whereas hospitals within low competition area were more likely to perform radiation therapy. Among localized disease patients, low hospital competition was associated with higher hazard of overall mortality (HR = 1.08, 95% CI = 1.07 - 1.10) and prostate cancer-specific mortality (HR = 1.13, 95% CI = 1.09 - 1.17) and higher odds of ER visits (OR = 1.13, 95% CI = 1.11 - 1.15). For advanced stage patients, low hospital competition was associated with higher hazard of overall mortality (HR = 1.11, 95% CI = 1.08 - 1.15) and prostate cancer-specific death (HR = 1.15, 95% CI = 1.09 - 1.18) and higher odds of ER visits (OR = 1.16, 95% CI = 1.11 - 1.22). Higher scores of the OI were associated with higher total medical costs per capita per year, and not associated with overall mortality. Conclusions: This novel study showed that higher hospital competition is associated with improved quality of care (reduced mortality, complications and ER visits) and increased/lower direct medical care cost among patients with localized or advanced stage prostate cancer. Policy measures should be implemented to improve hospital competition.

Modulation of T-cell Regulators Associated with Advanced Stage of Prostate Cancer

Modulation of T-cell Regulators Associated with Advanced Stage of Prostate Cancer